Sixteen-week virologic response rates to S/GSK1349572 (572), the experimental integrase inhibitor, exceeded those of efavirenz when either drug was taken with tenofovir/emtricitabine (TDF/FTC) or abacavir/lamivudine (ABC/3TC) [1]. Only 1 of 155 people dropped out of the three 572 groups because of side effects, while 4 of 50 withdrew from the efavirenz arm for that reason.

SPRING-1 researchers at several sites in Europe and the United States randomized more than 200 previously untreated people to one of three 572 doses (10, 25 or 50 mg once daily) or to standard-dose efavirenz with coformulated TDF/FTC (66%) or ABC/3TC (34%). Most study participants (86%) were men and 80% were white. Viral loads across the four study groups averaged about 25,000 to 40,000 copies; 26% had a viral load above 100,000 copies. CD4 counts averaged 324 in the whole study group, with little difference between treatment arms. Overall, then, this study group had moderately advanced disease.

One person taking 572 had a protocol-defined virologic failure, with a good initial virologic response, then a rebound at week 4. Only the M184V emtricitabine-related mutation emerged in this patient. The investigators suspected poor adherence. One person taking efavirenz did not have at least a 10-fold drop in viral load at week 4, though the viral load was declining steadily. No on-treatment resistance mutations could be detected, and the person remained in the trial.

Time to a viral load below 50 copies/mL was faster in each 572 arm than in the efavirenz arm (P < 0.001). After 4 weeks of therapy 66% taking the integrase inhibitor and 18% taking efavirenz had a viral load under 50 copies. It is unusual to have a planned 16-week analysis, though that strategy allowed researchers to demonstrate a faster response to 572 than to efavirenz.

A 16-week time-to-loss-of-virologic-response analysis determined that 51 of 53 people (96%) taking 10 mg of 572, 47 of 51 (92%) taking 25 mg, 46 of 51 (90%) taking 50 mg, and 30 of 50 (60%) taking efavirenz had a sub-50-copy viral load. Responses did not differ by gender or nucleoside backbone. Median CD4 gains were similar across arms at week 16: 289 with 10 mg of 572, 330 with 25 mg, 305 with 50 mg, and 308 with efavirenz.

Rates of drug-related moderate or worse adverse events were greater with efavirenz (18%) than with 572 (6%). No serious adverse events were considered related to 572. One serious adverse event, a suicide attempt, was considered related to efavirenz. One person (0.6%) taking 572 and 4 (8%) taking efavirenz dropped out of the study because of adverse events. Dyspepsia caused the dropout in the 572 arm. Average low-density lipoprotein cholesterol changed less with 572 (+0.066 mmol/L) than with efavirenz (+0.436 mmol/L).

The 50-mg dose of 572 will be tested in phase 3 trials in antiretroviral-naive people.